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Disrupted Murine Gut to Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models.

Disrupted Murine Gut to Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models.
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Chow EC, Quach HP, Zhang Y, Wang JZ, Evan DC, Li AP, Silva J, Tirona RG, Lai Y, Pang KS,


Chow EC, Quach HP, Zhang Y, Wang JZ, Evan DC, Li AP, Silva J, Tirona RG, Lai Y, Pang KS, (click to view)

Chow EC, Quach HP, Zhang Y, Wang JZ, Evan DC, Li AP, Silva J, Tirona RG, Lai Y, Pang KS,

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The Journal of pharmacology and experimental therapeutics 2016 Oct 27() pii jpet.116.236935
Abstract

The humanized liver mouse model is increasingly being exploited for human drug metabolism studies. However, its model stability, inter-communication between human hepatocytes and mouse non-parenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expression has not been investigated. We examined these issues in FRGN [Fah(-/-), Rag2(-/-), and IL-2rg(-/-) on NOD background] and chimeric mice: mFRGN, and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids), but lower TGFBR2 mRNA expression (10%) in human hepatocytes and other proliferative markers in mouse non-parenchymal cells (Tgf-β1) and cholangiocytes (Tgr5), suggestive of irregular regeneration processes in hFRGN livers. Changes in the murine intestine, kidney, and brain of hFRGN mice: in particular, induction of intestinal Fxr genes: Fgf15, Ibabp, Shp, and Ost-α, were observed. Proteomics revealed persistence of remnant murine proteins (Cyp7a1, other enzymes, and transporters) in hFRGN livers and likelihood of mouse activity. When compared to normal human liver tissues, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tβMCA- and tαMCA-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver FGFR4, as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, questioning use of the preparation for drug metabolism studies.

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